Pleuromutilin is a diterpene compound which has been isolated/identified in terms of its structure from Pleurotus mutilus Sacc. in 1951 and from Pleurotus passeckerianus Pil. in 1976, and the aglycone part thereof is referred to as mutilin (Non-Patent Documents 1 and 2). Its structural features include a three-ring structure consisting of a highly functionalized eight-membered ring fused with a hydroindanone structure and containing nine asymmetric carbon atoms.

Recently, the spread of intractable infectious diseases caused by various resistant bacteria has become a worldwide concern. It is obvious that pleuromutilin exhibits an antimicrobial activity by inhibiting the protein synthesis by acting on ribosomes in bacteria. Thus, pleuromutilin is useful as a new lead compound in the search for an agent for treating intractable infectious diseases. Among these, Tiamulin, as a pleuromutilin derivative, has long been used as an agent for treating infectious diseases in livestock; however, there are no reports of pleuromutilin or mutilin derivatives ever being applied to the treatment of infectious diseases in humans.
As such, the mutilin compound is a compound that has attracted worldwide attention in terms of two points, that is, its potent microbial activity and unique chemical structure. In recent years, several groups have reported novel mutilin derivatives. That is, for example, there have been reported a mutilincarbamoyloxy derivative (Patent Document 1), a pleuromutilin derivative (Patent Document 2), a pleuromutilin derivative (Patent Document 3), a 2-fluoromutilin derivative (Patent Document 4), a mutilin compound (Patent Document 5), a mutilin-14-ester derivative (Patent Document 6), an isoxazoline carboxylic acid derivative (Patent Document 7), a mutilin derivative (Patent Document 8), pleuromutilinbetaketoesters (Patent Document 9), a 2-hydroxymutilincarbamate derivative (Patent Document 10), a pleuromutilin derivative (Patent Document 11), a heterocyclic ester derivative (Patent Document 12), antimicrobially active mutilins (Patent Document 13), a novel pleuromutilin derivative (Patent Document 14), a pleuromutilin derivative (Patent Document 15), an organic compound (Patent Document 16), a pleuromutilin derivative having a hydroxyamino or acylaminocycloalkyl group (Patent Document 17), and a pleuromutilin derivative (Patent Document 18). All of these are patents claiming a pleuromutilin-derived vinyl group in which a substituent at the 12-position is naturally occurring, or an ethyl group resulting from the reduction of the vinyl group, but there have been no reports of a mutilin derivative having a structural feature in which a 1,4-dihydro-4-oxo-3-quinolonecarboxylic acid structure, a 1,4-dihydro-4-oxo-3-naphthylidinecarboxylic acid structure, or a pyridobenzoxazine structure, which is a heterocyclic aromatic ring carboxylic acid structure, is bonded via an acylcarbamoyl bond and a piperidine ring in a substituent at the 14-position. Thus, their antimicrobial activity is not known yet. In addition, as a mutilin derivative having a structural feature in which the substituents at the 12-position are various substituents other than a vinyl group or an ethyl group as shown in the present invention, there have been reported, for example, a mutilin derivative having a substituent at the 12-position (Patent Document 19), a mutilin derivative having a substituent at the 12-position having a pyridine ring in a substituent at the 14-position (Patent Document 20), and the like. All of these are characterized in that they have a 1-azabicyclo[2.2.1]heptane structure or a pyridine structure via an acylcarbamoyl bond in a substituent at the 14-position, and there have been no reports of a mutilin derivative having a structural feature in which a 1,4-dihydro-4-oxo-3-quinolonecarboxylic acid structure, a 1,4-dihydro-4-oxo-3-naphthylidinecarboxylic acid structure, or a pyridobenzoxazine structure, which is a heterocyclic aromatic ring carboxylic acid structure, is bonded via an acylcarbamoyl bond and a piperidine ring in a substituent at the 14-position.
As a mutilin derivative having a substituent at the 12-position and a 4-epimutilin derivative having a substituent at the 12-position, the following compounds are known. That is, a 4-epimutilin derivative having desethenyl at the 12-position (Non-Patent Document 3), a 4-epimutilin derivative having dimethyl substituted at the 12-position (Non-Patent Document 4), and a pleuromutilin derivative in which the stereochemistry of the substituent at the 12-position is opposite to that of a natural form and a pleuromutilin derivative having cyclopropyl substituted at the 12-position (Non-Patent Document 5) are known. All of these are the compounds in which the substituent at the 12-position as described in the present Patent Document is neither a naturally occurring vinyl group nor an ethyl group resulting from the reduction of the vinyl group, and there have been no reports of a mutilin derivative having a structural feature in which a 1,4-dihydro-4-oxo-3-quinolonecarboxylic acid structure, a 1,4-dihydro-4-oxo-3-naphthylidinecarboxylic acid structure, or a pyridobenzoxazine structure, which is a heterocyclic aromatic ring carboxylic acid structure, is bonded via an acylcarbamoyl bond and a piperidine ring in a substituent at the 14-position as shown in the present Patent Document.
Moreover, as for the mutilin derivative in which a hydroxyl group at the 11-position is protected, the following compounds are known. That is, a mutilin derivative (Non-Patent Document 6) is known, and in the present article, a mutilin form having acetoxy, dichloroacetoxy, and trifluoroacetoxy at the 11-position has been reported, and their compounds have become well-known. However, these compounds are not claimed in the present Patent Document, and the substituents at the 12-position as described in the present Patent Document are various substituents other than a vinyl group or an ethyl group. Further, there has been not reported a mutilin derivative having a structural feature in which a 1,4-dihydro-4-oxo-3-quinolonecarboxylic acid structure, a 1,4-dihydro-4-oxo-3-naphthylidinecarboxylic acid structure, or a pyridobenzoxazine structure, which is a heterocyclic aromatic ring carboxylic acid structure, is bonded via an acylcarbamoyl bond and a piperidine ring in a substituent at the 14-position as shown in the present Patent Document.
On the other hand, the production of the following mutilin derivatives for attaining an antimicrobial activity has been reported. Specifically, a mutilin 14-carbamate derivative (Non-Patent Document 7) has been known, and a compound having a naturally occurring vinyl group or an ethyl group resulting from the reduction of the vinyl group at the 12-position and a carbamoyl derivative at the 14-position, as described in the Non-Patent documents, is known. However, there have been no reports of a mutilin derivative having a structural feature in which a 1,4-dihydro-4-oxo-3-quinolonecarboxylic acid structure, a 1,4-dihydro-4-oxo-3-naphthylidinecarboxylic acid structure, or a pyridobenzoxazine structure, which is a heterocyclic aromatic ring carboxylic acid structure, is bonded via an acylcarbamoyl bond and a piperidine ring in a substituent at the 14-position as described in the present Patent Document.    Patent Document 1: Pamphlet of WO 1997025309, WO 1998005659    Patent Document 2: Pamphlet of WO 1999021855    Patent Document 3: Pamphlet of WO 1999051219    Patent Document 4: Pamphlet of WO 2000007974    Patent Document 5: Pamphlet of WO 2000027790    Patent Document 6: Pamphlet of WO 2000037074    Patent Document 7: Pamphlet of WO 2000073287    Patent Document 8: Pamphlet of WO 2001009095    Patent Document 9: Pamphlet of WO 2001014310    Patent Document 10: Pamphlet of WO 2001074788    Patent Document 11: Pamphlet of WO 2002004414    Patent Document 12: Pamphlet of WO 2002012199    Patent Document 13: Pamphlet of WO 2002022580    Patent Document 14: Pamphlet of WO 2002030929    Patent Document 15: Pamphlet of WO 2004089886    Patent Document 16: Pamphlet of WO 2007000001    Patent Document 17: Pamphlet of WO 2007000004    Patent Document 18: Pamphlet of WO 2007014409    Patent Document 19: Pamphlet of WO 2006070671    Patent Document 20: JP-A-2006-306727    Non-Patent Document 1: Kavanagh, F. et al., Proc. Natl. Acad. Sci. USA 1951, 37, 570-574.    Non-Patent Document 2: Knauseder, F. et al., J. Antibiot. 1976, 29, 125-131.    Non-Patent Document 3: Berner, H. et al., Tetrahedron 1981, 37, 915-919.    Non-Patent Document 4: Berner, H. et al., Tetrahedron 1983, 39, 1745-1748.    Non-Patent Document 5: Berner, H. et al., Monatsch. Chem. 1986, 117, 1073-1080.    Non-Patent Document 6: Birch, A. J. et al., Tetrahedron 1966, Suppl. 8, Part II, 359-387.    Non-Patent Document 7: Brooks, G. et al., Bioorg. Med. Chem. 2001, 9, 1221-1231.    Non-Patent Document 8: Green, T. W.; Wuts, P. G. M. “Protective Groups in Organic Synthesis”, 2nd Ed., Wiley Interscience Publication, John-Weiley & Sons, New York, 1991.    Non-Patent Document 9: Berner, H. et al., Tetrahedron 1980, 36, 1807-1811.    Non-Patent Document 10: J. Med. Chem. 1991, 34, 2726-2735.    Non-Patent Document 11: Tetrahedron Lett. 1991, 32, 1241-1244.    Non-Patent Document 12: J. Med. Chem. 1992, 35, 911.    Non-Patent Document 13: J. Chem. Soc. Perkin I. 1991, 1091-1097.    Non-Patent Document 14: J. Org. Chem. 2001, 66, 2526-2529.    Non-Patent Document 15: J. Org. Chem. 1962, 27, 3317.    Non-Patent Document 16: Chem. Ber. 1986, 119, 83.    Non-Patent Document 17: J. Gen. Chem. USSR, 1977, 2061-2067.    Non-Patent Document 18: J. Org. Chem. 1962, 27, 3742.